Project Summary Cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can disseminate to the brain, causing a highly fatal meningoencephalitis in immunocompromised patients, particularly those with AIDS, solid organ transplants, and cancer. Despite contemporary combination antifungal therapy, the survival rate for cryptococcosis approaches only 70%, and the at-risk population is expanding with the development of new immunosuppressive regimens for autoimmunity and cancer. Currently, the cellular and molecular mechanisms that regulate the mammalian immune response to C. neoformans are poorly defined. The candidate, Dr. Lena J. Heung, proposes a career development training program that will give her the knowledge and technical skills necessary to investigate the immune mechanisms of inflammatory monocytes in a murine model of pulmonary cryptococcosis. She has demonstrated that inflammatory monocytes play a detrimental role during the host response to C. neoformans by promoting fungal proliferation and eosinophil recruitment in the lung that ultimately lead to death. The aims of the project are to (1) evaluate how C. neoformans subverts inflammatory monocytes to promote fungal proliferation and (2) evaluate how inflammatory monocyte signaling pathways and cellular crosstalk disrupt anti-cryptoccocal immune responses. By using unique murine models and immunologic techniques to manipulate monocyte-specific functions, the proposed studies will determine if C. neoformans induces inflammatory monocytes to differentiate into cells that can be exploited as fungal reservoirs for dissemination and if C. neoformans-induced pulmonary eosinophilia is a pathologic process regulated by inflammatory monocytes through the signaling adapter DAP12 and cellular crosstalk with eosinophils. Defining these mechanisms will deepen our understanding of the signals that regulate pulmonary immunity to opportunistic fungi and inform novel opportunities for immunomodulatory interventions against cryptococcosis in vulnerable hosts. The proposed training will take place at Memorial Sloan Kettering Cancer Center, an institution that incorporates expertise from diverse scientific and clinical fields into an integrated research environment. The candidate will complete didactic and practical bench training in immunology with the guidance of an advisory committee composed of leading researchers in the field. Given her training as an Infectious Diseases physician and her PhD experience studying regulatory mechanisms of cryptococcal virulence, the candidate will develop a unique skill set that will enable her to tackle long-standing problems in medical mycology from a new perspective in order to create innovate solutions. Thus, at the end of the period of support, she will be poised to undertake a career as an independent physician-scientist in the field of fungal immunology.